The instant invention is directed to compounds useful for inhibiting protein tyrosine phosphatase PTP1B, preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds.
PTP1B belongs to a family of protein tyrosine phosphatases involved in the regulation of the cellular signalling mechanisms which are involved in metabolism, growth, proliferation and differentiation (Science 253:401-6 (1991)). Overexpression or altered activity of tyrosine phosphatase PTP1B can also contribute to the progression of various diseases (Ann. Rev. Biochem., 54:897-930 (1985)); and there is evidence which suggests inhibition of protein tyrosine phosphatase PTP1B is therapeutically beneficial for the treatment of diseases such as type I and II diabetes, obesity, autoimmune disease, acute and chronic inflammation, osteoporosis and various forms of cancer (J. Natl. Cancer Inst. 86:372-8 (1994); Mol. Cell. Biol. 14:6674-6682 (1994); The EMBO J. 12:1937-46 (1993); J. Biol. Chem. 269:30659-30667 (1994); and Biochemical Pharmacology 54:703-711 (1997)).
Because of the important role played by unregulated protein tyrosine phosphatase PTP1B in these diseases, agents which inhibit the enzyme have been the subject of active current research for their clinical potential. Reference is made to WO 99/46236, WO 99/46237, WO 99/46267 and WO 99/46268; and although each teaches certain heteroaryl and heterocycle amino(oxo)acetic acid protein tyrosine phosphatase PTP1B inhibitors, there is still a need for protein tyrosine phosphatase PTP1B inhibitors with modified or improved profiles of activity.
In the principle embodiment of the instant invention, therefore, are provided protein tyrosine phosphatase PTP1B inhibitors of formula (I): 
or therapeutically acceptable salts thereof, wherein
A is selected from N(H), O, S, Nxe2x95x90C(H), and C(H)xe2x95x90C(H);
B is selected from N and C(H);
with the proviso that when A is Nxe2x95x90C(H) or C(H)xe2x95x90C(H), B is C(H);
d is 0, 1, or 2;
L1 is a covalent bond or O;
L2 is selected from CH(R6) and CH2CH(R6);
R1 is selected from hydrogen and a carboxy protecting group;
R2 is selected from hydrogen, aminoalkyl, loweralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, (heterocycle)alkyl, hydroxyalkyl, and haloalkyl;
each R3 is independently selected from hydrogen, loweralkoxy, alkoxyalkyl, alkoxyalkenyl, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, arylalkyl, arylalkenyl, arylalkoxy, carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxamidoalkoxy, carboxy, carboxyalkyl, carboxyalkenyl, carboxyalkoxy, halo, heteroaryl, heteroarylalkyl, heteroarylalkenyl, and heteroarylalkoxy; or
A is C(H)xe2x95x90C(H), and two of R3 are on adjacent atoms and, taken together with the atoms to which they are attached, are phenyl, wherein the phenyl can be optionally substituted with one or two substituents independently selected from loweralkoxy, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, carboxamidoalkenyl, carboxamidoalkoxy, carboxyalkenyl, carboxyalkoxy, halo, and heteroarylalkoxy;
with the proviso that R3 is connected to a substitutable carbon atom;
R4 is selected from hydrogen, alkoxy, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, aryl, arylalkyl, arylalkoxy, arylthioxyalkyl, carboxamidoalkenyl, carboxamidoalkyl, carboxyalkyl, carboxylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroarylthioxyalkyl, halo, and R7-T-;
with the proviso that at when R4 is hydrogen, at least one of R3 is other than hydrogen;
R6 is selected from hydrogen, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, and (heterocycle)alkyl;
R7 is selected from aryl and heteroaryl;
T is selected from C(O)N(R8), N(R8)C(O), N(R8), OC(O)N(R8), N(R8)C(O)O, C(O), OC(O), (O)CO, O, S, S(O), SO2, C(O), OC(O)O, N(R8)C(O)N(R8), and C(O)OC(O);
wherein the asymmetric groups defining T are drawn with their left ends attached to R7 and their right ends attached to the ring and; and
R8 is selected from hydrogen and loweralkyl.
In another embodiment of the instant invention are provided compounds of formula (II) 
or therapeutically acceptable salts thereof, wherein R2 and R4 are defined previously, and R3 is selected from hydrogen and halo.
In a preferred embodiment of the compounds of formula (II), R2 is arylalkyl, and R4 is aryl.
In still another embodiment of the instant invention are provided compounds of formula (III) 
or therapeutically acceptable salts thereof, wherein R2 and R4 are defined previously; R3A is selected from hydrogen, loweralkoxy, alkoxycarbonylalkenyl, alkoxycarbonylalkoxy, aryl, carboxamidoalkenyl, carboxamidoalkoxy, carboxyalkenyl, carboxyalkoxy, halo, and heteroarylalkoxy; and R3B is selected from hydrogen and halo.
In a preferred embodiment of the compounds of formula (III), R2 is hydrogen, arylalkyl, cycloalkyl, or (heterocycle)alkyl; and R4 is aryl or heteroarylalkoxy.
In still another embodiment of the instant invention are provided compounds of formula (IV) 
or therapeutically acceptable salts thereof, wherein R2 and R4 are defined previously; R3b is selected from hydrogen and aryl; X is selected from CH2 and N(RX); and RX is selected from alkanoyl, alkylsulfonyl, arylsulfonyl, aryloyl, arylsulfonyl, carboxamidoalkyl, and (heterocycle)alkyl.
In a preferred embodiment of the compounds of formula (IV), R2 is hydrogen, arylalkyl, arylalkyl, (heterocycle)alkyl, or aminoalkyl; and R4 is hydrogen, halo, aryl, alkoxycarbonylalkenyl, carboxyalkenyl, heteroaryl, or carboxamidoalkenyl.
In still another embodiment of the instant invention are provided compounds of formula (V) 
or therapeutically acceptable salts thereof, wherein L1, R2, and R4 are defined previously; and R3b selected from hydrogen and heteroaryl.
In a preferred embodiment of the compounds of formula (V), L1 is a covalent bond or O; R2 is hydrogen; and R4 is hydrogen, halo, aryl, or heteroarylalkoxy.
In still another embodiment of the instant invention are provided compounds of formula (VI) 
or therapeutically acceptable salts thereof, wherein R2 and R4 are defined previously.
In a preferred embodiment of the compounds of formula (VI), R2 is hydroxyalkyl or arylalkyl and R4 is loweralkoxy, alkoxy, or aryl.
In still another embodiment of the instant invention are provided a method for preparing the compounds of
formula (I),
the method comprising:
(a) reacting a compound of formula (Ia) 
xe2x80x83or therapeutically acceptable salts thereof,
wherein
A, B, d, L1, L2, R1, and R2 are defined previously; and
R4P is coupling promoter group selected from the group consisting of chloride, bromide, trifluoromethanesulfonate, iodide, and hydroxy,
with a coupling partner, a base, and, optionally, a palladium catalyst; and
(b) optionally hydrolyzing the product of step (a).
In a preferred embodiment of the method, the coupling partner is selected from a substituted alkene, an optionally substituted arylboronic acid, an optionally substituted heteroarylboronic acid, an optionally substituted aryl trialkylstannane, an optionally substituted heteroaryl trialkylstannane, and an optionally substituted alkyl halide; and the palladium catalyst is selected from tetrakistriphenyl-phosphinepalladium(O), palladium(II) bis(triphenyl-phosphine)dichloride, and dipalladium tris(dibenzylidine-acetone).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (I).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (II).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (III).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (IV).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (V).
In still another embodiment of the instant invention is provided a method for inhibiting protein tyrosine phosphatase comprising administering a therapeutically effective amount of a compound of formula (VI).
In still another embodiment of the instant invention is provided a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (I).
In still another embodiment of the instant invention is provided a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (II).
In still another embodiment of the instant invention is provided a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (III).
In still another embodiment of the instant invention is provided a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (IV).
In still another embodiment of the instant invention is provided a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (V).
In still another embodiment of the instant invention is provided a method for treating diseases in a patient in recognized need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of formula (VI).
In still another embodiment of the instant invention is provided a composition comprising a compound of formula (I) in combination with a therapeutically acceptable excipient.
In still another embodiment of the instant invention is provided a composition comprising a compound of formula (II) in combination with a therapeutically acceptable excipient.
In still another embodiment of the instant invention is provided a composition comprising a compound of formula (III) in combination with a therapeutically acceptable excipient.
In still another embodiment of the instant invention is provided a composition comprising a compound of formula (IV) in combination with a therapeutically acceptable excipient.
In still another embodiment of the instant invention is provided a composition comprising a compound of formula (V) in combination with a therapeutically acceptable excipient.
In still another embodiment of the instant invention is provided a composition comprising a compound of formula (VI) in combination with a therapeutically acceptable excipient.
The instant invention provides a series of compounds which inhibit protein tyrosine phosphatase PTP1B. The compounds comprise a proximal, optionally substituted aryl or heteroaryl ring tethered through an optionally substituted linker to the nitrogen of an amino(oxo)acetic acid group. The proximal ring is optionally substituted phenyl, naphthyl, furanyl, thienyl, pyrrolyl, pyridyl, oxazolyl, or thiazolyl and has attached thereto at least one distal substituent other than hydrogen. The linker group connecting the proximal ring to the amino(oxo)acetic acid group is optionally substituted methylene or ethylene which can be optionally interrupted at the carbon-nitrogen juncture by an oxygen atom. When present, the preferred substituents on the linker group are cycloalkyl, especially cyclohexyl, and heterocycle, preferably optionally N-substituted piperidiny-4-yl.
As used throughout the specification of the instant invention, the following terms, as used herein, have the meanings indicated:
The term xe2x80x9calkanoyl,xe2x80x9d refers to a loweralkyl group attached to the parent molecular group through a carbonyl.
The term xe2x80x9calkanoyloxy,xe2x80x9d refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9calkoxy,xe2x80x9d refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9calkoxyalkenyl,xe2x80x9d refers to a loweralkoxy group attached to the parent molecular group through an alkenyl group.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d refers to a loweralkoxy group attached to the parent molecular group through a loweralkoxy group.
The term xe2x80x9calkoxyalkyl,xe2x80x9d refers to a loweralkoxy group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d refers to an ester group; e.g., an alkoxy group attached to the parent molecular group through a carbonyl.
The term xe2x80x9calkoxycarbonylalkyl,xe2x80x9d refers to an alkoxycarbonyl group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9calkoxycarbonylalkenyl,xe2x80x9d refers to an alkoxycarbonyl group attached to the parent molecular group through an alkenyl group.
The term xe2x80x9calkoxycarbonylalkoxy,xe2x80x9d refers to an alkoxycarbonyl group attached to the parent molecular group through a loweralkoxy group.
The term xe2x80x9calkenyl,xe2x80x9d refers to a monovalent straight or branched chain hydrocarbon radical having from two to six carbons and at least one carbonxe2x80x94carbon double bond.
The term xe2x80x9calkyl,xe2x80x9d refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to twenty carbons.
The term xe2x80x9calkylsulfonyl,xe2x80x9d refers to a loweralkyl group attached to the parent molecular group through a sulfonyl.
The term xe2x80x9calkynyl,xe2x80x9d refers to a monovalent straight or branched chain hydrocarbon group having from two to six carbons and at least one carbonxe2x80x94carbon triple bond.
The term xe2x80x9camino,xe2x80x9d refers to xe2x80x94NR9R10, wherein R9 and R10 are independently selected from hydrogen, loweralkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle, (heterocycle)alkyl, carboxycarbonyl, and an amino protecting group.
The term xe2x80x9caminoalkyl,xe2x80x9d refers to an amino group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9caminosulfonyl,xe2x80x9d refers to an amino group attached to the parent molecular group through a sulfonyl.
The terms xe2x80x9camino protecting group,xe2x80x9d or xe2x80x9cnitrogen protecting group,xe2x80x9d refer to selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of amino protecting groups include methoxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-butoxycarbonyl (Boc), para-methoxybenzyloxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methylsulfonyl, phenylsulfonyl, para-toluene-sulfonyl, trimethylsilyl, triethylsilyl, triphenylsilyl, and the like. Preferred nitrogen protecting groups of the invention are benzyloxycarbonyl (Cbz), formyl, acetyl, methylsulfonyl, benzoyl, and phenylsulfonyl.
The term xe2x80x9caryl,xe2x80x9d refers to an aromatic, carbocyclic ring or two fused aromatic, carbocyclic rings. These groups are exemplified by phenyl and naphthyl. The aryl groups of the invention can be optionally substituted with one, two, three, four, or five substituents independently selected from loweralkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, phenyl, heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and heterocycle selected from tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. The phenyl, the heteroaryl, and the heterocycle groups optionally substituting the aryl groups of the invention are attached to the parent aryl groups through either a covelent bond, a loweralkyl, an oxygen atom, or a carbonyl. The phenyl, the heteroaryl, and the heterocycle groups optionally substituting the aryl groups of the invention can also be further substituted with one, two, or three substituents independently selected from loweralkyl, loweralkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9carylboronic acid,xe2x80x9d refers to an aryl group to which is attached xe2x80x94B(OH)2.
The term xe2x80x9caryl trialkylstannane,xe2x80x9d refers to an aryl group to which is attached xe2x80x94Sn(R12)3, wherein each R12 is independently selected from loweralkyl.
The term xe2x80x9carylalkenyl,xe2x80x9d refers to an aryl group, attached to the parent molecular group through an alkenyl group.
The term xe2x80x9carylalkyl,xe2x80x9d refers to an aryl group attached to the parent molecular group through a loweralkyl group. The loweralkylene part of the arylalkyl group can be optionally substituted with a substituent selected from alkoxycarbonyl, hydroxy, carboxy, and alkanoyloxy.
The term xe2x80x9carylalkoxy,xe2x80x9d refers to an aryl group attached to the parent molecular group through a loweralkoxy group.
The term xe2x80x9cazido,xe2x80x9d refers to xe2x80x94N3.
The term xe2x80x9ccarbonyl,xe2x80x9d refers to xe2x80x94C(O)xe2x80x94.
The term xe2x80x9ccarboxamido,xe2x80x9d refers to an amide; e.g., an amino group attached to the parent molecular group through a carbonyl.
The term xe2x80x9ccarboxamidoalkenyl,xe2x80x9d refers to a carboxamido group attached to the parent molecular group through an alkenyl group.
The term xe2x80x9ccarboxamidoalkyl,xe2x80x9d refers to a carboxamido group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9ccarboxy,xe2x80x9d refers to xe2x80x94CO2H. The carboxy groups of the invention can be optionally protected by the replacement of the hydrogen atom thereof by a carboxy protecting group.
The term xe2x80x9ccarboxaldehyde,xe2x80x9d refers to xe2x80x94CHO.
The term xe2x80x9ccarboxy,xe2x80x9d refers to xe2x80x94CO2H. The carboxy groups of the invention can be optionally protected by the replacement of the hydrogen atom thereof by a carboxy protecting group.
The term xe2x80x9ccarboxyalkoxy,xe2x80x9d refers to a carboxy group attached to the parent molecular group through an alkoxy group.
The term xe2x80x9ccarboxycarbonyl,xe2x80x9d refers to a carboxy group connected to the parent molecular group through a carbonyl.
The term xe2x80x9ccarboxy protecting group,xe2x80x9d refers to selectively introducible and removable groups which protect carboxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups. Examples of carboxyl groups include loweralkyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), para-nitrobenzyl, para-methoxybenzyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloroethyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, arylalkoxyalkyl benzyloxymethyl 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, and the like. Preferred carboxyl protecting groups of the invention are lowerlkyl.
The term xe2x80x9ccyano,xe2x80x9d refers to xe2x80x94CN.
The term xe2x80x9ccycloalkenyl,xe2x80x9d refers to a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbons having at least one carbonxe2x80x94carbon double bond.
The term xe2x80x9ccycloalkenylalkyl,xe2x80x9d refers to a cycloalkenyl group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9ccycloalkyl,xe2x80x9d refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of three to twelve carbons. The cycloalkyl groups of the invention can be optionally substituted with one, two, three, or four substituents independently selected from loweralkyl, amino, alkoxy, alkoxycarbonyl, carboxaldehyde, carboxyl, halo, hydroxy, phenyl, heteroaryl, heterocycle, and oxo.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d refers to a cycloalkyl group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9chalo,xe2x80x9d refers to F, Cl, Br, or I.
The term xe2x80x9chaloalkyl,xe2x80x9d refers to a halo group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9cheteroaryl,xe2x80x9d refers to cyclic, aromatic groups having five or six atoms, wherein at least one atom is selected from nitrogen, oxygen, and sulfur, and the remaining atoms are carbon. The five-membered rings have two double bonds, and the six-membered rings have three double bonds. Heteroaryls of the invention are exemplified by furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the like. The heteroaryl groups of the invention are connected to the parent molecular group through a carbon atom in the ring or, as exemplified by imidazole and pyrazolyl, through either a carbon atom or nitrogen atom in the ring. The heteroaryl groups of the invention can be optionally substituted with one, two, or three radicals independently selected from loweralkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, thioalkoxy, a nitrogen protecting group, phenyl, and a heterocycle selected from tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. The phenyl and the heterocycle groups optionally substituting the heteroaryl groups of the invention are attached to the heteroaryl through either a covelent bond, a loweralkyl group, an oxygen, or a carbonyl group. The phenyl and the heterocycle groups optionally substituting the heteroaryl groups of the invention can also be further substituted with one, two, or three substituents independently selected from loweralkyl, loweralkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy. The heteroaryl groups of the invention can also be fused to one or two phenyl rings, in which case the heteroaryl group can be connected to the parent molecular group through either the heteroaryl part or the phenyl part of the fused ring system. Heteroaryl groups of this type are exemplified by quinolinyl, isoquinolinyl, benzodioxolyl, benzodioxinyl, dibenzo(b,d)furan, indolyl, and the like.
The term xe2x80x9cheteroarylalkoxy,xe2x80x9d refers to a heteroaryl attached to the parent molecular group through an alkoxy group.
The term xe2x80x9cheteroarylalkyl,xe2x80x9d refers to a heteroaryl group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9cheteroarylalkenyl,xe2x80x9d refers to a heteroaryl group attached to the parent molecular group through an alkenyl group.
The term xe2x80x9cheteroarylboronic acid,xe2x80x9d refers to a heteroaryl group to which is attached xe2x80x94B(OH)2.
The term xe2x80x9cheteroaryl trialkylstannane,xe2x80x9d refers to a heteroaryl group to which is attached xe2x80x94Sn(R12)3, wherein R12 is defined herein.
The term xe2x80x9cheteroarylthioxy,xe2x80x9d refers to a heteroaryl attached to the parent molecular group through a sulfur atom.
The term xe2x80x9cheteroarylthioxyalkyl,xe2x80x9d refers to a heteroarylthioxy group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9cheterocycle,xe2x80x9d refers to cyclic, non-aromatic, four-, five-, or six-membered groups containing at least one atom selected from oxygen, nitrogen, and sulfur. The four-membered rings have zero double bonds, the five-membered rings have zero or one double bonds, and the six-membered rings have zero, one, or two double bonds. Heterocycle groups of the invention are exemplified by dihydropyridinyl, imidazolinyl, morpholinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,3-dioxanyl, and the like. The heterocycles of the invention are attached to the parent molecular group through a carbon atom or nitrogen atom in the ring. The heterocycles of the invention can be optionally substituted one, two, or three substituents independently selected from loweralkyl, loweralkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxy, a nitrogen protecting group, perfluoroalkyl, perfluoroalkoxy, oxo, phenyl, and heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, and triazinyl. The phenyl and the heteroaryl groups optionally substituting the heterocycles of the invention are attached through a covelent bond, a loweralkyl group, an oxygen atom, or a carbonyl. The phenyl and the heteroaryl groups optionally substituting the heterocycles of the invention can also be further substituted with one, two, or three substituents independently selected from loweralkyl, loweralkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxy, perfluoroalkyl, and perfluoroalkoxy. The heterocycles of the invention can also be optionally fused to one or two phenyl rings, in which case the heterocycle can be connected to the parent molecular group through either the heterocycle part or the phenyl part of the fused ring system. Heterocycle groups of this type are exemplified by 1,3-benzodioxanyl, 1,3-benzodioxolyl, 2,4-dihydro-2H-1,4-benzoxazinyl, 1,3-benzothiazole, isoindoline, and the like.
The term xe2x80x9c(heterocycle)alkyl,xe2x80x9d refers to a heterocycle attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9chydroxy,xe2x80x9d refers to xe2x80x94OH. The hydroxy groups of the invention can be optionally protected by replacement of the hydrogen atom thereof with a hydroxy protecting group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d refers to a hydroxyl group attached to the parent molecular group through a loweralkyl group.
The term xe2x80x9chydroxy protecting group,xe2x80x9d refers to selectively introducible and removable groups which protect hydroxy groups against undesirable side reactions during synthetic procedures. Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,
2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.
The term xe2x80x9cloweralkoxy,xe2x80x9d refers to a loweralkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9cloweralkyl,xe2x80x9d refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons.
The term xe2x80x9cloweralkylene,xe2x80x9d refers to a divalent straight or branched chain saturated hydrocarbon diradical having from one to six carbons.
The term xe2x80x9cnitro,xe2x80x9d refers to xe2x80x94NO2.
The term xe2x80x9coxo,xe2x80x9d refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
The term xe2x80x9cperfluoroalkoxy,xe2x80x9d refers to a perfluoroalkyl group attached to the parent group through an oxygen atom.
The term xe2x80x9cperfluoroalkyl,xe2x80x9d refers to a loweralkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
The instant compounds can exist as therapeutically acceptable salts. The term xe2x80x9ctherapeutically acceptable salt,xe2x80x9d refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of diseases without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the amino group of the compounds with a suitable acid. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalic, maleic, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulphuric, phosphoric, and the like. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
Basic addition salts can be prepared during the final isolation and purification of the instant compounds by reaction the carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,Nxe2x80x2-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like, are contemplated as being within the scope of the instant invention.
The instant compounds can also exist as therapeutically acceptable prodrugs. The term xe2x80x9ctherapeutically acceptable prodrug,xe2x80x9d refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
The term xe2x80x9cprodrug,xe2x80x9d refers to compounds which are rapidly transformed in vivo to parent compounds of formulas (I)-(VI) for example, by hydrolysis in blood.
The term xe2x80x9csulfonyl,xe2x80x9d refers to xe2x80x94SO2xe2x80x94.
The term xe2x80x9cthioalkoxy,xe2x80x9d refers to a loweralkyl group attached to the parent molecular group through a sulfur atom.
Asymmetric centers can exist in the instant compounds. Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well-known in the art.
Geometric isomers can exist in the instant compounds The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbonxe2x80x94carbon double bond, a cycloalkyl, or a heterocycle. Substituents around a carbonxe2x80x94carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycle are designated as being of cis or trans configuration.
Therapeutic compositions of the instant compounds comprise an effective amount of the same formulated with one or more therapeutically acceptable excipients. The term xe2x80x9ctherapeutically acceptable excipient,xe2x80x9d refers to a non-toxic, solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Examples of therapeutically acceptable excipients include sugars; cellulose and derivatives thereof; oils; glycols; solutions; buffering, coloring, releasing, coating, sweetening, flavoring, and perfuming agents; and the like. These therapeutic compositions can be administered parenterally, intracisternally, orally, rectally, or intraperitoneally.
Liquid dosage forms for oral administration of the instant compounds comprise formulations of the same as emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the compounds, the liquid dosage forms can contain diluents and/or solubilizing or emulsifying agents. Besides inert diluents, the oral compositions can include wetting, emulsifying, sweetening, flavoring, and perfuming agents.
Injectable preparations of the instant compounds comprise sterile, injectable, aqueous and oleaginous solutions, suspensions or emulsions, any of which can be optionally formulated with parenterally acceptable diluents, dispersing, wetting, or suspending agents. These injectable preparations can be sterilized by filtration through a bacterial-retaining filter or formulated with sterilizing agents which dissolve or disperse in the injectable media.
PTP inhibition by the instant compounds can be delayed by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compounds depends upon their rate of dissolution which, in turn, depends on their crystallinity. Delayed absorption of a parenterally administered compound can be accomplished by dissolving or suspending the compound in oil. Injectable depot forms of the compounds can also be prepared by microencapsulating the same in biodegradable polymers. Depending upon the ratio of compound to polymer and the nature of the polymer employed, the rate of release can be controlled. Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions which are compatible with body tissues.
Solid dosage forms for oral administration of the instant compounds include capsules, tablets, pills, powders, and granules. In such forms, the compound is mixed with at least one inert, therapeutically acceptable excipient such as a carrier, filler, extender, disintegrating agent, solution retarding agent, wetting agent, absorbent, or lubricant. With capsules, tablets, and pills, the excipient can also contain buffering agents. Suppositories for rectal administration can be prepared by mixing the compounds with a suitable nonirritating excipient which is solid at ordinary temperature but fluid in the rectum.
The instant compounds can be micro-encapsulated with one or more of the excipients discussed previously. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric and release-controlling. In these forms, the compounds can be mixed with at least one inert diluent and can optionally comprise tableting lubricants and aids. Capsules can also optionally contain opacifying agents which delay release of the compounds in a desired part of the intestinal tract.
Transdermal patches have the added advantage of providing controlled delivery of the instant compounds to the body. Such dosage forms are prepared by dissolving or dispensing the compounds in the proper medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin, and the rate of absorption can be controlled by providing a rate controlling membrane or by dispersing the compounds in a polymer matrix or gel.
Diseases caused or exacerbated by protein tyrosine phosphatase PTP1B activity are treated or prevented in a patient by administering to the same a therapeutically effective amount of the instant compounds in such an amount and for such time as is necessary to achieve the desired result. The term xe2x80x9ctherapeutically effective amount,xe2x80x9d refers to a sufficient amount of the compound to treat protein tyrosine phosphatase PTP1B activity at a reasonable benefit/risk ratio applicable to any medical treatment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, rate of excretion; the duration of the treatment; and drugs used in combination or coincidental therapy.
The total daily dose of the instant compounds in single or divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions can contain such amounts or submultiples thereof of the compounds to make up the daily dose. In general, treatment regimens comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses.
Specific compounds of the invention include, but are not limited to,
((2-(4-bromophenyl)-2-cyclohexylethyl)amino)(oxo)acetic acid,
(benzyl(2-(4-bromophenyl)-2-cyclohexylethyl)amino)-(oxo)acetic acid,
(((4-bromophenyl)(cyclohexyl)methoxy)amino)(oxo)acetic acid,
((cyclohexyl(3-(2-quinolinyl)phenyl)methoxy)amino) (oxo)acetic acid,
(benzyl(2,3-dichloro-4-(1-naphthyl)benzyl)amino) (oxo)acetic acid,
N-benzyl-2-hydroxy-N-((4,1xe2x80x2-binaphth-1-yl)methyl)-amino)(oxo)acetic acid,
(benzyl(2-chloro-4-(1-naphthyl)benzyl)amino)(oxo)acetic acid,
(benzyl((4-bromo-5-(1-naphthyl)-2-thienyl)methyl)-amino)(oxo)acetic acid,
(benzyl((5-(1-naphthyl)-2-thienyl)methyl)amino)-(oxo)acetic acid,
(benzyl(4-(2-quinolinylmethoxy)benzyl)amino)(oxo)acetic acid,
oxo((2-phenylethyl)(4-(2-quinolinylmethoxy)benzyl)-amino)acetic acid,
(cyclohexyl(4-(2-quinolinylmethoxy)benzyl)amino)-(oxo)acetic acid,
(benzyl(2-methoxy-4-(1-naphthyl)benzyl)amino)-(oxo)acetic acid,
((2-hydroxyethyl)((4,1xe2x80x2-binaphth-1-yl)methyl)amino)-(oxo)acetic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(2-(4-morpholinyl)ethyl)amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)-amino)(oxo)acetic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(2-phenyl-ethyl)amino)(oxo)acetic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(2-(3,4-dimethoxyphenyl)ethyl)amino)(oxo)acetic acid,
(benzyl(2-(carboxymethoxy)-4-(1-naphthyl)benzyl)amino)-(oxo)acetic acid,
(benzyl(2-(2-tert-butoxy-2-oxoethoxy)-4-(1-naphthyl)-benzyl)amino)(oxo)acetic acid,
3-(((2-((benzyl(carboxycarbonyl)amino)methyl)-5-(1-naphthyl)phenoxy)acetyl)amino)benzoic acid,
(benzyl(2-(2-(((4-(methoxycarbonyl)cyclohexyl)methyl)-amino)-2-oxoethoxy)-4-(1-naphthyl)benzyl)amino)(oxo)acetic acid,
(benzyl(4-(1-naphthyl)-2-(2-oxo-2-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)ethoxy)benzyl)amino)(oxo)acetic acid,
5-((2-((benzyl(carboxycarbonyl)amino)methyl)-5-(1-naphthyl)-phenoxy)methyl)-2-furoic acid,
((cyclohexyl(4-(2-quinolinylmethoxy)phenyl)methyl)-amino)(oxo)acetic acid,
((2-methoxy-4-(1-naphthyl)benzyl)(2-phenylethyl)amino)-(oxo)acetic acid,
((2,3-dichloro-4-(1-naphthyl)benzyl)(2-phenylethyl)-amino)(oxo)acetic acid,
((2-(4-(((carboxycarbonyl)amino)sulfonyl)phenyl)-ethyl)(2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)amino)-(oxo)acetic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(3-(2-oxo-1-pyrrolidinyl)propyl)amino)(oxo)acetic acid,
(benzyl((5-(1-naphthyl)(1,1xe2x80x2-biphenyl)-2-yl)methyl)-amino)(oxo)acetic acid,
(benzyl((4xe2x80x2-formyl-5-(1-naphthyl)(1,1xe2x80x2-biphenyl)-2-yl)-methyl)amino)(oxo)acetic acid,
(benzyl(2-((1E)-3-tert-butoxy-3-oxo-1-propenyl)-4-(1-naphthyl)benzyl)amino)(oxo)acetic acid,
(2E)-3-(2-((benzyl(carboxycarbonyl)amino)methyl)-5-(1-naphthyl)phenyl)-2-propenoic acid,
(benzyl(2-(4-((1E)-3-tert-butoxy-3-oxo-1-propenyl)-phenyl)-2-cyclohexylethyl)amino)(oxo)acetic acid,
((2,3-dichloro-4-(1-naphthyl)benzyl)(2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl)amino)(oxo)acetic acid,
(((1,1xe2x80x2-biphenyl)-4-yl(cyclohexyl)methoxy)amino)-(oxo)acetic acid,
(benzyl(4-(1-naphthyl)-2-((1E)-3-oxo-3-((3-(2-oxo-1-pyrrolidinyl)propyl)amino)-1-propenyl)benzyl)amino)-(oxo)acetic acid,
(2E)-3-(4-(2-(benzyl(carboxycarbonyl)amino)-1-cyclohexyl-ethyl)phenyl)-2-propenoic acid,
(benzyl(2-cyclohexyl-2-(4-((1E)-3-(4-hydroxy-3,5-diphenyl-anilino)-3-oxo-1-propenyl)phenyl)ethyl)amino)-(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-(3-(4-hydroxy-3,5-diphenyl-anilino)-3-oxopropyl)phenyl}ethyl)amino)(oxo)acetic acid,
((2-(1-(tert-butoxycarbonyl)-4-piperidinyl)-2-(4-(1-naphthyl)phenyl)ethyl)(2-phenylethyl)amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(3xe2x80x2-phenyl(1,1xe2x80x2-biphenyl)-4-yl)-ethyl)amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-dibenzo(b,d)furan-2-ylphenyl)ethyl)amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-(8-quinolinyl)phenyl)ethyl)-amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl)ethyl)amino)(oxo)acetic acid,
((2-(4-(1-naphthyl)phenyl)-2-(4-piperidinyl)ethyl)(2-phenyl-ethyl)amino)(oxo)acetic acid trifluoroacetate,
((2-(1-acetyl-4-piperidinyl)-2-(4-(1-naphthyl)-phenyl)ethyl)-(2-phenylethyl)amino)(oxo)acetic acid,
((2-(1-(methylsulfonyl)-4-piperidinyl)-2-(4-(1-naphthyl)-phenyl)ethyl)(2-phenylethyl)amino)(oxo)acetic acid,
((2-(1-benzoyl-4-piperidinyl)-2-(4-(1-naphthyl)phenyl)-ethyl)(2-phenylethyl)amino)(oxo)acetic acid,
((2-(4-(1-naphthyl)phenyl)-2-(1-(phenylsulfonyl)-4-piperidinyl)ethyl)(2-phenylethyl)amino)(oxo)acetic acid,
((2-(1-(2-(diethylamino)-2-oxoethyl)-4-piperidinyl)-2-(4-(1-naphthyl)phenyl)ethyl)(2-phenylethyl)amino)(oxo)acetic acid,
5-((4-(2-((carboxycarbonyl)(2-phenylethyl)amino)-1-(4-(1-naphthyl)phenyl)ethyl)-1-piperidinyl)methyl)-2-furoic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(2-((5-nitro-2-pyridinyl)amino)ethyl)amino)(oxo)acetic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(2-(1-pyrrolidinyl)ethyl)amino)(oxo)acetic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(2-(1H-indol-3-yl)ethyl)amino)(oxo)acetic acid,
((2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)(2-hydroxy-2-phenylethyl)amino)(oxo)acetic acid,
(((1S)-1-benzyl-2-hydroxyethyl)(2-cyclohexyl-2-(4-(1-naphthyl)phenyl)ethyl)amino)-(oxo)acetic acid,
(2S)-2-((carboxycarbonyl)(2-cyclohexyl-2-(4-(1-naphthyl)-phenyl)ethyl)amino)-3-phenylpropanoic acid,
(benzyl(2-(4-((1E)-3-((1,1xe2x80x2-biphenyl)-4-ylamino)-3-oxo-1-propenyl)phenyl)-2-cyclohexylethyl)amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-((1E)-3-(3,5-ditert-butyl-anilino)-3-oxo-1-propenyl)phenyl)ethyl)amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-((1E)-3-oxo-3-(4-phenoxyanilino)-1-propenyl)phenyl)ethyl)amino)(oxo)acetic acid,
(benzyl(2-cyclohexyl-2-(4-((1E)-3-(4-(2,3-dimethylphenyl)-1-piperazinyl)-3-oxo-1-propenyl)phenyl)-ethyl)amino)(oxo)acetic acid,
((2-(4-((1E)-3-(4-benzhydryl-1-piperazinyl)-3-oxo-1-propenyl)phenyl)-2-cyclohexylethyl)(benzyl)amino)(oxo)acetic acid,
oxo((2-phenylethyl)((4,1xe2x80x2-binaphth-1-yl)methyl)amino)-acetic acid,
(((4-((1,3-benzothiazol-2-ylsulfanyl)methyl)phenyl)-(cyclohexyl)methoxy)amino)(oxo)acetic acid,
((cyclohexyl(4-(2,3-dihydro-1,4-benzodioxin-6-yl)-phenyl)methoxy)amino)(oxo)acetic acid,
(((4-(decyloxy)-1-naphthyl)methyl)(2-phenylethyl)-amino)(oxo)acetic acid,
(((4-(octadecyloxy)-1-naphthyl)methyl)(2-phenylethyl)-amino)(oxo)acetic acid,
((2-(1,1xe2x80x2-biphenyl)-3-yl-2-cyclohexylethyl)(2-phenyl-ethyl)amino)(oxo)acetic acid,
(((4-butoxy-1-naphthyl)methyl)(2-phenylethyl)amino)-(oxo)acetic acid,
oxo((2-phenylethyl)((4-(tetradecyloxy)-1-naphthyl)-methyl)amino)acetic acid,
((2-cyclohexyl-2-(3-(1-naphthyl)phenyl)ethyl)(2-phenyl-ethyl)amino)(oxo)acetic acid,
((2-cyclohexyl-2-(3-(2-naphthyl)phenyl)ethyl)(2-phenyl-ethyl)amino)(oxo)acetic acid, and
((2-cyclohexyl-2-(3xe2x80x2-phenyl(1,1xe2x80x2-biphenyl)-3-yl)-ethyl)(2-phenylethyl)amino)(oxo)acetic acid.
Human protein tyrosine phosphatase PTP1B (1-321) was expressed in E. coli BL21(DE3). The cell paste was resuspended in 4 cell paste volumes of lysis buffer containing 100 mM MES (pH 6.5), 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mM PMSF, 20 U/mL Benzonase, 0.5 mg/mL lysozyme, and 1 mM MgCl2 and incubated for 35 minutes at room temperature. The cells were lysed at 11,000 psi using a Rannie homogenizer, and the homogenate was clarified in a Beckman GSA rotor at 10,000xc3x97g for 30 minutes at 4xc2x0 C. The supernatant was loaded onto a 5xc3x9721 cm S-Sepharose-FF column (Amersham Pharmacia Biotech) preequilibrated with 5 column volumes of buffer containing 100 mM MES (pH 6.5), 100 mM NaCl, 1 mM EDTA, and 1 mM DTT and eluted with 10 column volumes of the same. The fractions (28 mL each) were assayed for protein by 10-20% Tris-Glycine SDS-PAGE. Fractions which contained  greater than 95% protein tyrosine phosphatase PTP1B were combined.
Protein tyrosine phosphatase PTP1B activity was determined by measuring the phosphate release from triphosphorylated peptide which corresponds to residues 1135-1156 of the b-subunit of the human insulin receptor (bIRK substrate) as described in Nature, 313, 756-761 (1985). Protein tyrosine phosphatase PTP1B activity was determined in a final assay volume of 50 xcexcL containing 50 mM Tris HCl, 50 mM Tris Base, 150 mM NaCl, 3 mM DTT, 0.1 mg/mL bovine serum albumin (Sigma), 2 nM protein tyrosine phosphatase PTP1B(1-321), and 16 xcexcM bIRK substrate. Various concentrations of test compounds in 5 xcexcL of 10% DMSO were incubated for 5 minutes at room temperature with 20 xcexcL of protein tyrosine phosphatase PTP1B enzyme in a flat-bottom microtiter plate (Costar). The phosphatase reaction was initiated by the addition of bIRK substrate (25 xcexcL) and proceeded for 10 minutes at room temperature. The reaction was terminated by the addition of 100 xcexcL of malachite green (Upstate Biotechnology Inc.) containing 0.01% Tween-20. After a 5 minute incubation, quantitation of free phosphate released from the bIRK substrate was determined in a Beckman Biomek Plate Reader by measuring the absorbence of the malachite green at 650 nm.
The instant compounds were found to inhibit protein tyrosine phosphatase PTP1B with inhibitory potencies in a range of about of about 3 xcexcM to about 100 xcexcM. In a preferred range, the compounds inhibited protein tyrosine phosphatase PTP1B with inhibitory potencies in a range of about of about 29 xcexcM to about 60 xcexcM; and in a more preferred range, the compounds inhibited protein tyrosine phosphatase PTP1B with inhibitory potencies in a range of about of about 3 xcexcM to about 21 xcexcM.
As protein tyrosine phosphatase PTP1B inhibitors, therefore, the instant compounds are useful for treating diseases caused by overexpressed or altered protein tyrosine phosphatase PTP1B activity. These diseases include autoimmune diseases, acute and chronic inflammatory diseases, osteoporosis, obesity, cancer, malignant diseases, type I and type II diabetes.
The compounds and processes of the instant invention will be better understood in connection with the following synthetic schemes which illustrate methods by which the compounds can be prepared. The compounds can be prepared by a number of synthetic procedures, and representative procedures are shown in Schemes 1-6. The groups A, B, d, L1, L2, R1, R2, R3, and R4, are previously defined, and the groups X1 and X2 are define below. It will be appreciated by a skilled practitioner that selective protection and deprotection steps can be conducted, depending on the nature of A, B, d, L1, L2, R1, R2, R3, and R4, to successfully complete the syntheses of the compounds. A discussion of protecting groups is provided in Greene and Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 3rd Ed., John Wiley and Son, Inc., (1999). It will also be appreciated that the compounds can be synthesized by substitution of the appropriate reactants and reagents and that the steps themselves can be conducted in varying order. A discussion
of functional group transformations is provided in Larock, xe2x80x9cComprehensive Organic Transformations. A Guide to Functional Group Preparations,xe2x80x9d 2nd. Ed., John Wiley and Sons, Inc. New York (1999).
Abbreviations used in the descriptions of the schemes and the examples that follow are: dba for dibenzylidine acetone; DCI for direct chemical ionization; DEAD for diethyl azodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIBAL-H for diisobutylaluminum hydride; DME for dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; EDCI for 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride; ESI for electrospray chemical ionization; HMPA for hexamethylphosphoramide; MTBE for methyl tert-butyl ether; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TLC for thin layer chromatography; py for pyridine; and Ts for para-toluenesulfonyl. 
As shown in Scheme 1, compounds of formula (1) wherein R4P is an R4 precursor such as hydroxy, triflate, bromo, or iodo, can be converted to compounds of formula (2) by treatment of the former with coupling partners.
The compounds of formula (1) are commercially available or can be prepared by means well-known in the art, such as, for example, deprotonation of the corresponding aryl or heteroaryl group with a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, n-butyllithium, sec-butyllithium, tert-butyllithium, or lithium diisopropylamide and treatment of the resulting anion with a reagent which introduces the desired functionality. For example, treatment of the anion with DMF will introduce a carboxaldehyde group at the first deprotonation site; treatment of the anion with electrophilic halogenating reagents such as bromine, N-bromosuccinimide, iodine, or N-iodosuccinimide will introduce the corresponding halide that site; treatment of the anion with an oxidizing agent such as MoO5.py.HMPA will introduce a hydroxy group at that site; and treatment of the anion with electrophilic nitrogen reagents such as ClNH2, (C6H5)2P(O)NH2, Br2/NaN3, and TsN3. The substitution pattern of carboxaldehyde and R4P on what will become the proximal ring of the instant compounds can be predetermined by the different acidities of the protons on the aryl or heteroaryl ring starting materials and the strength of the base used for the deprotination. Subsequent deprotonation and derivitization reactions can be accomplished by treatment of the starting material with a second equivalent of base followed by treatment of the anion with the appropriate electrophile.
When R4P is bromo, iodo, or triflate, the coupling partners comprise substituted alkenes, optionally substituted arylboronic acids, optionally substituted heteroarylboronic acids, optionally substituted aryl trialkylstannanes, and optionally substituted heteroaryl trialkylstannanes. The reactions are conducted with a base such as cesium fluoride, sodium carbonate, or potassium carbonate and palladium catalysts such as Pd(PPh3)4, Pd(PPh3)2Cl2, or Pd2(dba)3 in solvents such as acetonitrile, THF, DME, DMF, benzene, toluene, or mixtures thereof at temperatures of about 25xc2x0 C. to about 120xc2x0 C. The reagents and reaction conditions selected depend on the nature of the coupling partners. The reaction times are typically about 1 to about 18 hours.
When R4P is hydroxy, the coupling partners comprise optionally substituted alkyl halides in the presence of a base such as sodium hydride or potassium hydride at reaction temperatures are about 0xc2x0 C. to about 50xc2x0 C. The reaction times are typically about 1 to about 18 hours.
Elaboration of R4P to compounds wherein R4 is R7-T- can be accomplished by treatment of the appropriately substituted starting material with the corresponding isocyanates, chloroformates, acid halides, and carbamoyl chlorides. The reagents, solvents, and reaction conditions such as temperatures and reaction times for these transformations are well-known in the art. 
As shown in Scheme 2, compounds of formula (2) can be converted to compounds of formula (3) by treatment of the former with amines in the presence of reducing agents. Representative reducing agents include sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride. The reactions are conducted in solvents such as methanol, ethanol, isopropanol, or mixtures thereof at temperatures of about 0xc2x0 C. to about 30xc2x0 C. Reaction times are typically about 1 to about 24 hours. 
As shown in Scheme 3, compounds of formula (4) can be converted to compounds of formula (5) by treatment of the former with base and compounds of formula R6xe2x80x94X1, wherein X1 represents a leaving group such as halide, sulfonate, or triflate. Representative bases include sodium hydride, potassium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and LDA. Solvents used in these reactions include THF, DMF, DMSO, MTBE, diethyl ether, or mixtures thereof. The reaction temperatures are about 0xc2x0 C. to 30xc2x0 C. and depend on the method chosen. Reaction times are typically about 1 to about 12 hours.
Compounds of formula (5) can be converted to compounds of formula (6) using the conditions described for the conversion of compounds of formula (1) to compounds of formula (2) as described in in Scheme 1.
Compounds of formula (6) can be converted to compounds of formula (7) by treatment of the former with reducing agents followed by hydrolysis with aqueous acid. Representative reducing agents include SnCl2/HCl lithium aluminum hydride, and DIBAL-H. Representative acids include HCl, HBr, TFA, or mixtures thereof. Examples of solvents used in these reactions include toluene, THF, and hexanes. The reaction temperatures are about xe2x88x9278xc2x0 C. to about 0xc2x0 C. and depend on the method chosen.
Compounds of formula (7) can be converted to compounds of formula (8) using the conditions described for the conversion of compounds of formula (2) to compounds of formula (3) as described in in Scheme 2.
As shown in Scheme 4, compounds of formula (2) can be converted to compounds of formula (9) by treatment with compounds of formula R6xe2x80x94X2, wherein X2 represents lithium, magnesium halide, and zinc halide. Examples of solvents used in these reactions include THF, MTBE, diethyl ether, and mixtures thereof. Reaction temperatures are about xe2x88x9278xc2x0 C. to about 25xc2x0 C. and depend on the method chosen. Reaction times are typically about 1 to about 18 hours.
Conversion of compounds of formula (9) to compounds of formula (10) can be accomplished by treatment of the former with N-hydroxyphthalimide, a trialkylphosphine or triarylphosphine, and a diazo compound. Representative trialkylphosphines include tributylphosphine and trimethylphosphine; representative triarylphosphines include triphenylphosphine and tri-o-tolylphosphine; and representative diazo compounds include DEAD and DIAD. Examples of solvents used in this reaction include THF, MTBE, diethyl ether, benzene, toluene, or mixtures thereof. The reaction temperatures are about 25xc2x0 C. to about 35xc2x0 C. Reaction times are typically about 4 to about 18 hours.
The conversion of compounds of formula (10) to compounds of formula (11) can be accomplished by treatment of the former with hydrazine. Examples of solvents used in this reaction include ethanol, methanol, water, dioxane, and mixtures thereof. The reaction temperatures are about 60xc2x0 C. to about 120xc2x0 C. Reaction times are typically about 15 minutes to about 1 hour. 
As shown in Scheme 5, compounds of formula (12) can be converted to compounds of formula (I) by treatment of the former with an alkyl oxalyl chloride and base. Representative bases include diisopropylethylamine, triethylamine, and pyridine. Examples of solvents include DME, dioxane, and DMF. The reaction temperatures are about xe2x88x925xc2x0 C. to about 25xc2x0 C., and the reaction times are typically about 30 minutes to about 12 hours.
Intraconversion of compounds of formula (I) can be accomplished by hydrolysis with aqueous base followed by treatment with acid. Representative bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide. Examples of acids include hydrochloric acid, sulfuric acid, and nitric acid. The reaction temperatures are about 25xc2x0 C. to about 100xc2x0 C. and the reaction times are typically about 1 to about 4 hours. 
As shown in Scheme 6, compounds of formula (13) can be converted to compounds of formula (Ia) by the chemistry described for the conversion of compounds of formula (12) to compounds of formula (I) in Scheme 5. The conversion of the compounds of formula (Ia) to compounds of formula (I) can be accomplished by the chemistry described for the conversion of compounds of formula (1) to compounds of formula (2) in Scheme 1.
The invention will now be described in connection with other particularly preferred embodiments of Schemes 1-5, which are not intended to limit its scope. On the contrary, the invention covers all alternatives, modifications, and equivalents which are included within the scope of the claims. Thus, the following examples will illustrate an especially preferred practice of the invention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.